TY  - JOUR
A1  - Willems, Sabine
A1  - Kilu, Whitney
A1  - Ni, Xiaomin
A1  - Chaikuad, Apirat
A1  - Knapp, Stefan
A1  - Heering, Jan Peter
A1  - Merk, Daniel
T1  - The orphan nuclear receptor Nurr1 is responsive to non-steroidal anti-inflammatory drugs
T2  - Communications chemistry
N2  - Nuclear receptor related 1 (Nurr1) is an orphan ligand-activated transcription factor and considered as neuroprotective transcriptional regulator with great potential as therapeutic target for neurodegenerative diseases. However, the collection of available Nurr1 modulators and mechanistic understanding of Nurr1 are limited. Here, we report the discovery of several structurally diverse non-steroidal anti-inflammatory drugs as inverse Nurr1 agonists demonstrating that Nurr1 activity can be regulated bidirectionally. As chemical tools, these ligands enable unraveling the co-regulatory network of Nurr1 and the mode of action distinguishing agonists from inverse agonists. In addition to its ability to dimerize, we observe an ability of Nurr1 to recruit several canonical nuclear receptor co-regulators in a ligand-dependent fashion. Distinct dimerization states and co-regulator interaction patterns arise as discriminating factors of Nurr1 agonists and inverse agonists. Our results contribute a valuable collection of Nurr1 modulators and relevant mechanistic insights for future Nurr1 target validation and drug discovery.
KW  - Chemical tools
KW  - Drug screening
KW  - Medicinal chemistry
Y1  - 2020
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/55508
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-555086
SN  - 2399-3669
N1  - This article is licensed under a Creative Commons Attribution 4.0 International License http://creativecommons.org/licenses/by/4.0/.
VL  - 3
IS  - art. 85
SP  - 1
EP  - 12
PB  - Macmillan Publishers Limited, part of Springer Nature
CY  - London
ER  -